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Mol Pharm. 2016 Feb 1;13(2):568-77. doi: 10.1021/acs.molpharmaceut.5b00789. Epub 2015 Dec 28.

Luteolin Inhibits Hepatitis B Virus Replication through Extracellular Signal-Regulated Kinase-Mediated Down-Regulation of Hepatocyte Nuclear Factor 4α Expression.

Bai L1,2, Nong Y1,2, Shi Y1,2, Liu M1,2, Yan L1,2, Shang J1,2, Huang F3, Lin Y4, Tang H1,2.

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Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu 610041, China.
Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, China.
Department of Forensic Pathology, Medical School of Basic and Forensic Sciences, Sichuan University , Chengdu 610041, China.
Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute , 2425 Ridgecrest Dr. SE, Albuquerque, New Mexico 87108, United States.


Whether luteolin inhibits HBV replication has not been validated and the underlying mechanism of which has never been elucidated. In this study, we show that luteolin reduces HBV DNA replication in HepG2.2.15 cells. Luteolin effectively inhibited the expression of hepatocyte nuclear factor 4α (HNF4α) and its binding to the HBV promoters in HepG2.2.15 cells. While the extracellular signal-regulated kinase (ERK) was activated by luteolin, inhibition of ERK abolished luteolin-induced HNF4α suppression. Consistently, blocking ERK attenuated the anti-HBV activity of luteolin. In a HBV replication mouse model, luteolin decreased the levels of HBsAg, HBeAg, HBV DNA replication intermediates, and the HBsAg and HBcAg expression. Taken together, our results validated the anti-HBV activity of luteolin in both in vitro and in vivo studies and established a signaling cascade consisting of ERK and HNF4α for inhibition of HBV replication by luteolin, which may be exploited for clinical application of luteolin for anti-HBV therapy.


extracellular signal-regulated kinase; flavonoid; hepatitis B virus; hepatocyte nuclear factor 4α; replication

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